Production of alpha-fluorocarboxylic acid lactones



United States Patent 3,227,732 PRUDUCTION 0F a-FLUORQCARBGXYLIC ACHD LACTDNES Rudoit Tschesehe, Bonn-Rodgers, and Hans Machieidt,

lfionn, Gennany, assignors to 01in Mathieson Chemical Corporation, New York, N.Y., a corporation of Vi ginia No Draw'mg. Original application Oct. 31, 1962, Ser. No. 234,524. Divided and this application Apr. 9, 1 964, Ser. No. 364,053 Ciahns priority, application Germany, Nov. 11, 1961, T 21,095 2 Claims. (Cl. 260-3435) This application is a division of application Serial No. 234,524, filed October 31, 1962.

This invention relates to the production of zx-fiuOIO substituted carboxylic acids and esters.

Aliphatic u-fiUOI'OCflIbOXYllC acid esters are dificult to obtain by conventional methods especially in good yield. tI has now been found that such esters may be readily produced in good yield from a-fiuoro-fl-ketocarboxylic acid esters in alcoholic solution in the presence of catalytic amounts of strong bases. Since the a-fluoro-fl-ketocarboxylic acid esters are easily obtained by the reaction of a-substituted-B-keto esters with perchloryl fluoride in the presence of a strong base, such as sodium ethoxide, potassium t-butoxide and the like, this process has particular advantage.

This invention is applicable to the conversion of aliphatic esters of Formula Ia to products of Formula Ila or to the conversion of cyclic esters of Formula II; to products of Formula lib as follows:

in the above formulas R represents lower alkyl, carbocylic aryl or carbocylic arall-ryl. R represents alkyl, ali-cenyl or carbocyclic aryl, carbocyclic aralkyl, or carbocyclic aralkenyl, each of which may contain a functional group such as hydroxy, acyloxy, carbonyl or carbalkoxy. R represents lower alkyl. The symbol n represents 1 or 2.

All-:yl groups included in the symbols (including the alkyl moiety of the aralkyl and caroalkoxy groups) are straight or branched chain saturated aliphatic groups having up to about 18 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, amyl, isoamyl, hexyl, octyl, stearyl, palmityl and the like, the lower alkyl groups being preferred. The alkenyl groups are monounsatured aliphatic groups of the same character. Carbocyclic aryl groups include for example, phenyl, o-tolyl, p-carbethoxyphenyl, m-acetylphenyl and the like. The aralkyl and aralkenyl groups are preferably phenyl substituted alkyl and alkenyl groups of the type described.

The conversion of compounds of the Formulas Ia and lb to the respective products Ila and 11b is effected in alcoholic solution, e.g. a lower alkanol such as methanol, ethanol or the like, in the presence of a strong base such as alkali metal alkanolate, e.g. sodium methoxide, sodium ethoxide or the like. Catalytic amounts of bases, e.g. about 0.01 to 0.5, preferably about 0.1 to 0.2, molar equivalents of base in relation to keto ester,

are sufiicient to provide good yields. The mixture may be heated to accelerate the reaction, if desired; a temperature up to reflux temperature may be used.

If, however, the fluorination of the unsubstituted-,8- keto carboxylic acid ester, from which the compounds In and 1b are derived, are treated with the perchloryl fluoride (in about equimolecular proportion) in the presence of an excess of the strong base referred to above at a temperature between 40 and C., then the products Ila and Ill) are obtained directly.

The ester serves as an intermediate for the corresponding a-fluorinated acid to which it may be converted by hydrolysis with an alkali metal hydroxide such as sodium hydroxide or alkaline earth metal hydroxide.

The cc-flllOIOCElIbOXYllC acids are physiologically active substances useful as anti-metabolites in that they are orally effective hypocholesteremic agents which inhibit the bisosynthesis of cholesterol and regulate the level of cholesterol in the blood being useful in the treatment of atherosclerosis and similar conditions involving excess of cholesterol.

The following examples are illustrative of this invention. All temperatures are expressed on the centigrade scale.

EXAMPLE 1 2flz10r0-5-methylhexanoic acid ethyl ester 23.2 grams of a-fluoro-a-isoamyl-acetoacetic acid ethyl ester in a solution of 0.5 gram of sodium in ml. of absolute ethanol are refluxed for three hours. After the solution has cooled and Water has been added, the neutral fraction is extracted several times with petroleum ether. The combined petroleum ether phases yield, after washing with some water, distilling oil the solvent and distilling the remaining oil, in vacuo, 12.3 grams (67%) of 2-fluoro-5-methylhexanoic acid ester, B2 79-80".

Calcd. for C9H17FO2 (176.8): C, 61.4; H, 9.72. Found: C, 61.29; H, 9.65.

55 grams of Z-fluoro-S-methylhexanoic acid ethyl ester are refluxed with a solution of 12.1 grams of sodium hydroxide in 1 liter of methanol and water at the ratio of 1:1 for five hours. After cooling, distilling oit the methanol in vacuo and the addition of sulfuric acid, the organic acid is extracted several times with petroleum ether. The combined petroleum ether phases yield, after distilling oif the solvent and distilling the residue in vacuo, 28.2 grams (61%) of crystalline 2-fluoro-5-methylhexanoic acid, B.P. Recrystallized from the petroleum ether, long leaflets, M.P. 47-48, are obtained.

Calcd. for C l-l FO (148.2): C, 56.72; H, 8.84; F, 12.86. Found: C, 56.60; H, 9.03; F, 12.66.

EXAMPLE 3 Z-fluoro-S-methyl-4-hexen0ic acid ethyl ester A. 80.5 grams of u-fluoro-a-(3-methyl-2-butenyl) acetoacetic acid ethyl ester are refluxed with a solution of 500 mg. of sodium in 250 ml. of absolute ethanol for two hours. After cooling and the addition of an equal volume of water to the solution, the neutral fraction is extracted several times with petroleum ether. After washing of the combined pertoleum ether phases, drying over magnesuim sulfate and distilling off the solvent, the residue yields, when distilled in vacuo, 65.2 grams (85%) of 2-fiuoro-5-methyl-4-hexenoic acid ethyl ester, B.P. 84-87.

Calcd. for C H FO (174.2); C, 62.04; H, 8.68. Found: C, 62.02; H, 8.68.

B. 168 grams (1 mol) of a-(3-methyl-2-butenyl) acetoacetic acid ethyl ester are dropped, with cooling, into a solution 27.6 grams of sodium (1.2 gram-atoms) in 800 ml. of absolute ethanol and then 102 grams (1 mol) of perchloryl fluoride are added, with stirring, at 30- 40. Separation of sodium chlorate occurs immediately. After heating to 50 for three hours, the solution is separated from the sodium chlorate by filtering under suction, concentrated to about 300 ml. in vacuo and, after 400 ml. of water have been added, the neutral fraction is extracted several times with chloroform. After washing the combined chloroform phases with water, drying and distilling off the solvent, fractional distillation of the residue yields 125 grams (72%) of 2-fluoro-5-methyl- 4-hexenoic acid ethyl ester, B.P. 87. This is gaschromatographically identical with the preceding product.

EXAMPLE 4 2-flu0r0-5-methyl-4-hexenoic acid 30 grams of 2-fluoro-5-methyl-4-hexenoic acid ethyl ester are refluxed with a solution of 8.25 grams of sodium hydroxide in 400 ml. of methanol and water at the ratio 1:1 for three hours. After distilling off the methanol in vacuo and adding sulfuric acid, the organic acid is isolated by extraction with chloroform. The residue obtained after distilling off the solvent yields, when dis tilled in vacuo, 21.7 grams (86%) of crystalline 2-fluoro- 5-methyl-4-hexenoic acid, B.P. 65. Recrystallized from the petroleum ether, long leaflets of M.P. 3435 are obtained.

Calcd. for C H FO (146.2): C, 57.48; H, 7.57. Found: C, 56.99; H, 7.44.

EXAMPLE 2-flu0ro-5,9-dimethyl-8-decenoic acid, ethyl ester 85.0 grams of a-fluoro-a-(3,7-dimethyl-6-octenyl) acetoacetic acid ethyl ester are refluxed with a solution of 500 mg. of sodium in 300 ml. of absolute ethanol for three hours. After cooling and adding 300 ml. of water, the neutral fraction is extracted several times with petroleum ether. The combined petroleum ether phases yield, after washing, drying, distilling off the solvent and distilling of the residue in vacuo, 63 grams (87%) of 2- fluoro-5,9-dimethyl-8-decenoic acid ethyl ester, B.P. 70-74.

Calcd. for C H FO (244.3): C, 68.82; H, 10.32. Found: C, 68.98; H, 10.03.

EXAMPLE 6 a-FIMOIO-y-b utyrolactone 73.5 grams of a-fluoro-a-acetyl-y-butyrolactone are refluxed with a solution of 1.16 grams of sodium in 200 ml. of absolute ethanol for one hour. After cooling, 300 ml. of water are added and the lactone is extracted with chloroform several times. After washing the combined chloroform phases in some water, drying and distilling off the solvent, an oil remains, which, after vacuum distillation yields 37.2 grams (71%) of a-fluoro-y-butyrolactone, B.P. 114.

Calcd. for C H FO (104.1): C, 45.98; H, 4.81. Found: C, 45.68; H, 4.89.

EXAMPLE 7 a-Fluorosuccinic acid diethyl ester 63 grams of a-fiuoro-a-acetylsuccinic acid diethyl ester are refluxed with a solution of 1.5 grams of sodium in 300 m1. of absolute ethanol for one hour. After cool ing and adding 300 ml. of water the fluorinated ester is extracted several times with chloroform. After washing the combined chloroform phases with water, drying over MgSO and distilling off the solvent, distillation of the residue yields 32.2 grams (62%) of u-fluorosuccinic acid diethyl ester, B.P.

Calcd. for C H FO (192.2): C, 50.01; H, 6.82. Found: C, 50.23; H, 6.98.

What is claimed is:

1. A process for the production of compounds of the formula wherein R is a member of the group consisting of alkyl, alkenyl, carbocyclic aryl, carbocyclic aralkyl and carbocyclic aralkenyl, and n is an integer from 1 to 2, which comprises treating a compound of the formula wherein R and n are as above defined and R is a member of the group consisting of alkyl, carbocyclic aryl and carbocyclic aralkyl, with a catalytic amount of strong base in alcoholic solution.

2. A process as in claim 1 wherein the base is alkali metal alkanolate and the alcohol is a lower alkanol.

No references cited.

WALTER A. MODANCE, Primary Examiner. 

1. A PROCESS FOR THE PRODUCTION OF COMPOUNDS OF THE FORMULA 